Concepts of Microbial Disease
The term symbiosis or “living together,” is an association between two or more species. There are three types (Figure 7.1). Mutualism is a condition in which both species benefit (for example, lichens represent a mutualistic relationship between a fungus and an alga; Figure 7.3). In commensalism, one species beneﬁts but the other neither beneﬁts nor is harmed (the human normal flora receive nutrients and shelter, but the human host neither benefits nor is harmed; Figure 7.4). Parasitism is an association in which the parasite lives at the expense of the other species, the host (here parasite refers to all microbial pathogens).
The distinctions between mutualism, commensalism, and parasitism are a type of “see-saw” relationship, in which a commensal relationship can turn parasitic (Figure 7.5). For example, the normal flora can be opportunistic pathogens, causing disease in the immunocompromised. E. coli, when introduced to the normally sterile peritoneum (by a pierced intestine), can cause a potentially fatal peritonitis (Figure 7.6).
Parasitism: A Way of Life
Parasites are the cause of infectious disease, as the parasite (microbe) lives at the expense of the host and, by doing so, causes damage to the host. Parasitism results in a constant negotiation between the parasite and the host, as each evolves in response to the other.
Microbes as Agents of Disease
Before microbes were known to even exist, many infectious diseases caused infection and massive human suffering. The bubonic plague, a bacterial disease, killed millions in the fourteenth century. The smallpox virus was a scourge for centuries, until it was eradicated through immunization in 1980. By the nineteenth century, observations led to an understanding that nonhygienic conditions and disease vectors (including rodents, mice, ﬂeas, ticks, lice, and mosquitoes) foster the prevalence of disease. In the late 1800s, Louis Pasteur proved that microbes were responsible for fowl cholera and anthrax in sheep. Robert Koch established that tuberculosis was caused by a bacterium, later named Mycobacterium tuberculosis. Koch’s work extended well beyond tuberculosis and led to the development of Koch’s postulates, that are still used to establish that a particular organism is the cause of a particular disease (Figure 7.7). His postulates have proved invaluable to medicine, but the requirement to culture the agent on artificial media has been impossible for some bacterial diseases (e.g., leprosy and syphilis) and for all viral and prion diseases.
Microbial Mechanisms of Disease
Infectious diseases may range in severity from subclinical (asymptomatic), to mild, moderate, severe, or lethal. The chance of acquiring an infection depends upon three major factors: (n) dose, the number of microbes encountered, (V) virulence, virulence factors, and (R) resistance, host immunity—summarized as D = nV/R, with D representing the severity of the infection.
Pathogenicity and Virulence
For most bacteria there is a minimal infective dose (ID) necessary for infection. More virulent organisms have smaller IDs than less virulent. Ten tubercle bacilli may cause infection, but a million or more of the less virulent cholera bacterium may be required for infection. The LD50 is a laboratory measurement of virulence (Figure 7.8), which determines the number of microbes necessary to kill 50% of the animals infected. Pathogenic microbes have the ability to cause disease. Virulence is a measure of pathogenicity and encompasses those factors (toxins, etc.) that enable the pathogen to overcome host defense mechanisms and to multiply and cause damage. Pathogens have adaptive defensive strategies that allow them to escape destruction by the host immune system and offensive strategies (Table 7.1) that result in damage to the host. The distinction between these two strategies is not always clear; however, more virulent organisms tend to have more effective strategies than less virulent pathogens.
Many pathogens have cell surface molecules called adhesins (Figure 7.9), which enable adherence to cell receptors at a portal of entry (skin and mucous membranes of the mouth, nose, genital tract, etc.). The bacterium that causes gonorrhea has adhesins that enable the bacterium to resist being washed away by the flow of urine. Bacteria lacking adhesins would tend to be swept away and unable to colonize cell surfaces at the portal of entry.
Capsules and Other Structures
Capsules interfere with phagocytosis. Experiments have shown that removal of the capsule from encapsulated bacteria makes them more susceptible to being phagocytosed by immune cells (Figure 7.10). Streptococci that cause strep throat have M protein on their surface; mutants lacking M protein are readily phagocytosed. Bacterial virulence is due to a combination of virulence factors, of which capsule and M protein are just two examples.
The causative agents of influenza, African sleeping sickness (Figure 7.11), relapsing fever, and gonorrhea are all masters of antigenic disguise. Many microbial surface proteins are recognized as being foreign antigens by the immune system. Specific antibody molecules made by the host can target these antigens, marking the microbe for destruction. Antigenic variation is an effective strategy that allows microbes to evade this antibody defense system.
Helicobacter pylori, the bacterium that causes peptic ulcers, secretes the enzyme urease, which enables it to survive in the highly acidic environment of the stomach. Urease breaks urea into ammonia and carbon dioxide. The ammonia helps to neutralize the stomach acid, enabling H. pylori to survive, protected by a “cloud” of ammonia (Figure 7.12). In addition to this defensive strategy, H. pylori secretes a variety of toxins that cause tissue damage and ulcer formation.
Some pathogens secrete enzymes, called spreading factors, which destroy host tissues, enabling bacteria to spread to adjacent sites. Hyaluronidase is an enzyme that breaks down the hyaluronic acid content of connective tissue, reducing its viscosity and fostering the spread of microbes deeper into the tissues. Collagenase is another example of a spreading factor; it breaks down collagen, a vital part of connective tissue, resulting in gas gangrene and massive areas of necrotic (dead) tissue. Hemolysins destroy red blood cells through destruction of cell membranes, and leukocidins destroy white blood cells. Coagulase forms a network of threads around bacteria, affording protection against phagocytosis. Kinases later break down these clots, allowing the microbes to spread.
Toxins are important virulence factors for many pathogens; they are classiﬁed as either exotoxins or endotoxins. These toxins differ from each other in their chemical composition, modes of action, and nature of their release. Exotoxins are protein molecules that are synthesized within the microorganism and secreted into the host tissues by the microbe. The ability to produce toxins is called toxigenicity. Exotoxins are readily soluble in body ﬂuids and are rapidly transported throughout the body. There are three principal types: cytotoxins, which kill or damage host cells, neurotoxins, which interfere with transmission of nerve impulses, and enterotoxins which affect the cells lining the gastrointestinal tract, leading to diarrhea (Table 7.12).
Toxoids are toxins that have been detoxiﬁed but retain their antigenicity (ability to elicit specific host antibodies). Toxoids are used to immunize against toxigenic microbes. Many potentially fatal toxigenic bacterial diseases are caused by the toxin and not by the presence of the bacterium; these include botulism, diphtheria, tetanus, and cholera.
Many toxins follow the AB model of toxin activity (Figure 7.13). Such toxins have two subunits, the A, or active subunit, and the B, or binding subunit. The A subunit has the toxic enzymatic activity, but is incapable of binding to cells; purified B subunits can bind to cells, but are non-toxic. Two of the best-known exotoxins cause the potentially fatal bacterial diseases botulism and tetanus. Botulism causes a flaccid muscle paralysis, while tetanus works in the reverse, causing a spastic muscle paralysis (Figure 7.14).
Some toxins are carried by a lysogenic prophage. For example, presence of the tox gene in lysogenized C. diphtheriae encodes an exotoxin that is responsible for the disease diphtheria. When these bacteria are “cured” (the phage is removed), toxin production no longer takes place. The genes for other exotoxins, including erythrogenic, botulinum, and cholera toxins, are carried on prophages.
Endotoxins are very different from exotoxins (Table 7.3). Endotoxins are part of the lipopolysaccharide molecule in the outer membrane of gram-negative cells (Figure 4.2). Endotoxin is only released when these cells are disrupted, or during cell multiplication (in small amounts). All endotoxins produce the same host response (shock, chills, fever, weakness, formation of small blood clots, and possibly death). Ironically, individuals with gram-negative infections may experience these symptoms if certain antibiotics are used in treatment, because of endotoxin release from dying cells.
Virulence Mechanisms of Nonbacterial Pathogens
As obligate intracellular parasites, viruses can hide from components of the immune system. The ability of some viruses (inﬂuenza virus) to change their antigen coats is a defense against antibodies. On the offensive side, viruses can lyse the host cell by producing large numbers of replicating viruses, shutting down the host cell’s protein synthesis, damaging the cell membrane of the host, and inhibiting host cell metabolism. Viruses must attach to specific host molecules (not to avoid being washed away, but to enter the cell). For example, HIV docks with strategic T lymphocytes of the immune system, causing the infected individual to become severely immunocompromised.
Many protozoans, fungi, and helminthes (worms) are pathogens whose virulence factors are diverse. Many fungi secrete toxins and enzymes that cause damage to host cell tissues and aid in their invasion. Giardia, a water-transmitted protozoan parasite that causes severe diarrhea, attaches to cells lining the small intestine by a virulence factor called an adhesive or sucking disk (Figure 7.9). The protozoan responsible for malaria infects and reproduces within host red blood cells causing their rupture, and the trypanosome protozoan that causes sleeping sickness exhibits antigenic variation, a defensive strategy of virulence that inﬂuenza virus also uses. Helminths are large extracellular parasitic worms that can physically obstruct lymph circulation, leading to grotesque swellings in the legs and other body structures, a condition called elephantiasis. Ascaris worms can “ball up,” obstruct the intestinal tract, and migrate into the liver. Waste products of helminths can cause toxic and immunologic reactions.
Stages of Microbial Disease
The five general stages of microbial disease are summarized in Table 7.4.
The incubation stage is the time between the pathogen’s access to the body through a portal of entry and the display of signs and symptoms. The incubation time is consistent in some diseases but variable in others, ranging from two to four hours in staphylococcal food poisoning, two to three weeks in chicken pox, and six months to 12 years in AIDS.
The prodromal stage is relatively short and not always obvious. The symptoms are typically mild or vague (tiredness, headache, muscle aches, and malaise). In some infections, the individual may be contagious during this stage.
During the illness stage the disease is most severe, accompanied by characteristic signs and symptoms that may include fever, nausea, vomiting, chills, headache, muscle pain, fatigue, swollen lymph nodes, and a rash. This is the time during which the pathogen’s virulence factors are competing with the host’s immune system. Depending on the outcome, either recovery will be complete, or impairment or death of the host will result.
Stage of Decline
If the host’s immune system wins out, the signs and symptoms begin to disappear; the body starts to return to normal
During the convalescence, recovery takes place, strength is regained, repair of damaged tissues takes place, and rashes disappear. In some cases, healthy and chronic carrier states develop, as might happen with cholera and typhoid fever (this carrier state can persist for years).
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